(1) Field of the Invention
The present invention relates generally to spherical polymer matrices for the controlled release of various drug(s) or other selected agents. More particularly, this invention describes methodology for preparing highly porous spherical polymer matrices with preselected incorporated agents, e.g., therapeutics, dispersed within the confines of the pores therein for controlled delivery to target physiological systems and resulting biodegradable microspheric drug carrier or controlled delivery systems.
(2) State of the Art
A wide variety of microencapsulation drug delivery systems have been developed heretofore for the rate controlled release of therapeutics or other agents. For instance, considerable research has been devoted to incorporating therapeutic agents into polyesters such as poly.epsilon.-caprolactone), poly(.epsilon.-caprolactone-CO-DL-lactic acid), poly(DL-lactic acid), poly(DL-lactic acid-CO-glycolic acid) and poly.epsilon.-caprolactone-CO-glycolic acid) in which release was diffusion controlled. See, for example, Pitt, C. G. (Pitt, C. G., Gratzl, M. M., Jeffcoat, A. R., Zweidinger, R., Schindler, A., Sustained Drug Delivery Systems. II. Factors Affecting Release Rates from Poly(.epsilon.-caprolactone) and Related Biodegradable Polyesters. J. Pharm. Sci., 68, 1534 (1979). These systems were fabricated as films and capsules and the results suggest that the devices can be prepared to erode after release of the drug is essentially completed. Degradation of at least the polyesters has been reported to proceed by random hydrolytic cleavage of ester linkages by an autocatalytic process the rate of chain cleavage being influenced by chemical and morphological factors.
Sustained release systems of antimalarial agents and sulfadiazine in glycolic-lactic acid copolymers have also been reported. Wise, D. L., Gesser, J. D., McCormick, G. J., Sustained Release of a Dual Anti-malarial System, J. Pharm. Pharmacol., 31, 201 (1979). Wise, D. L., McCormick, G. J., Willet, G. P., Anderson, L. C., Sustained Release of an Antimalarial Drug Using a Copolymer of Glucolic/Lactic Acid, Life Sci., 19, 867 (1976). Wise, D. L. , McCormick, G. J., Willet, G. P., Anderson, L. C., Howes, J. F., J. Pharm. Pharmacol., 30, 686 (1978). Methods reported by the foregoing investigators involved dissolving the agents in a suitable solvent and either spray drying or casting films according to usual methods and evaporating the solvent. Various narcotic antagonists and steroids have been incorporated in films and implanted in rats [e.g., see Woodland, J. H. R., Yolles, S., Blake, D. A., Helrich, M., Meyer, F.J., Long-Acting Delivery Systems for Narcotic Antagonists:I. J. Med. Chem., 16, 897 (1973). Jackanicz, T. M., Nash, H. A., Wise, D. L., Gregory, J. B., Polylactic Acid as a Biodegradable Carrier for Contraceptive Steroids, Contraception, 8, 227 (1973). Anderson, L. C., Wise, D. L., Howes, J. F., An Injectable Sustained Release Fertility Control System, Contraception, 13, 375 (1976)] and incorporated into particles injected subcutaneously [Yolles, S., Time-Release Depot for Anticancer Drugs: Release of Drugs Covalently Bonded to Polymers, J. Parent, Drug Assoc., 32, 188 (1978)]. The release of a number of anti-tumor agents has been evaluated in implantable systems as reported in [Yolles, S., Time-Release Depot for Anticancer Drugs: Release of Drugs Covalently Bonded to Polymers, J. Parent, Drug Assoc., 32, 188 (1978)], and the antibiotic Mitomycin C has been encapsulated in microspherical carriers of gelatin and administered intraveneously [Yoshioka, T., Hashida, M., Muranishi, S., and Sezaki, H., Specific Delivery of Mitomycin C to Liver, Spleen and Lung: Nano-and Microspherical Carriers of Gelatin. Intern J. Pharm., 81, 131 (1981)]and the effect of size on in vivo distribution and the potential for antibiotic targeting discussed. The size distribution of the microspheres (i.e. 5-30 .mu.m) reported in the last mentioned publication was very broad, especially for intravenous administration. Recently the in-vitro release of local anesthetics from polylactic acid spheres prepared by a solvent evaporation process has, likewise, been reported [Wakiyama, N., Kaxuhiko, J., Nakano, M., Influence of Physicochemical Properties of Polylactic Acid on the Characteristics and In Vitro Release Patterns of Polylactic Acid Microspheres Containing Local Anesthetics, Chem. Pharm. Bull., 30, 2621 (1982)]. The patterns of release from these polylactic acid spheres were characterized by the various degrees of degradation of the polymer as well as solubilities of loaded drugs although no attempt was apparently made to evaluate this parameter. Additionally, it is apparent that the solubility of the drug played an important role in the rate and extent of release. Scanning electron photomicrographs also revealed varying degrees of erosion and deformation of the spheres after release.
It will be seen from the foregoing that while the controlled release delivery of pharmaceuticals or other agents from heretofore described polymeric systems has been principally limited to oral, topical or implantable systems in which the considerations relative to pore size and/or cell size within the carrier matrix as well as the overall dimensions of the microspheres to be administered along with the rate of release and the relative absorption rate from a bioavailability standpoint are distinctly different from the evaluation parameters involved in the utilization of these microsphere delivery systems for parenteral, i.e., intravenous, intraarterial, intraocular or inhalation administration routes to which the present invention is particularly applicable.